Project Summary An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. While a number of mGlu5 NAMs have been advanced to clinical testing, the previous compounds all suffer from serious shortcomings, including poor pharmacokinetic properties and toxicity that have prevented their further development. Therefore, these prior compounds have not allowed for clinical studies to rigorously test this hypothesis in patients. We have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have excellent properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, we anticipate that our compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions. It will be essential that new pain drugs do not suffer from abuse liability or severe toxicity that would prevent chronic administration, and these issues are addressed in the current research plan. We propose to conduct lead optimization, in vivo pharmacokinetic (PK), and pharmacodynamic (PD) studies to identify suitable preclinical candidates. Preclinical proof of concept studies will be conducted to test the hypothesis that mGlu5 NAMs will be efficacious in the treatment of pain. Additionally, we will perform positron emission tomography studies to determine in vivo receptor occupancy on lead candidates. Receptor occupancy data, along with in vivo PK data, will be used to determine the appropriate dosing regimen for efficacy studies in rodent models of inflammatory, neuropathic, and visceral pain. Efficacy data from these studies will be used to clearly establish a PK/PD/CNS receptor occupancy relationship and inform human dose projections. To ensure mGlu5 NAMs are void of the addictive qualities associated with opioid drugs, self-administration studies will be conducted to evaluate abuse liability. If UG3 milestones are met, a UH3 phase, in partnership with NIH contractors, will include all chemistry, manufacturing and control (CMC) and safety pharmacology and toxicology studies required to prepare a preclinical candidate (PCC) for an investigation new drug (IND) application submission.